1. Field of the Invention
The crystalline cephalosporin monohydrate of the present invention possesses in general the usual attributes of that family of antibacterial agents and is particularly useful in pharmaceutical formulations for treatment of bacterial infections by oral administration.
2. Description of the Prior Art
The cephalosporin compound 7-[D-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4 -carboxylic acid is disclosed and claimed in U.K. Pat. No. 1,240,687 (see also U.S. Pat. No. 3,489,752). The above-named compound has been given the generic name cefadroxil and has the structural formula ##STR1##
Cefadroxil is active as a broad spectrum antibiotic effective in controlling diseases caused by a wide variety of Gram-positive and Gram-negative microorganisms. It is of particular interest as an oral cephalosporin antibiotic.
U.K. Pat. No. 1,240,687 discloses the preparation of cefadroxil by acylation of 7-aminodesacetoxycephalosporanic acid (7-ADCA) with an amino-protected derivative of D(-)-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetic acid. Of the various amino-protected acylating agents disclosed, the highest yields were obtained with D-(-)-.alpha.-(p-hydroxyphenyl)-.alpha.-(t-butoxycarbonylamino)acetic acid via the so-called t-BOC method. The yields in this process, however, were not as high as are desired for commercial production and the reagent used in the t-BOC process is very expensive.
U.S. Pat. No. 3,985,741 discloses preparation of cefadroxil by acylation of 7-ADCA with the mixed anhydride of D-(-)-.alpha.-(p-hydroxyphenyl)glycine when the latter's .alpha.-amino group has been blocked blocked with a .beta.-keto compound such as methyl acetoacetate. This process, while having certain definite advantages over the t-BOC procedure, is still not as efficient as is desired for a commercially feasible production process.
Production of cefadroxil by enzymatic hydrolysis of its O-acetyl derivative is described in Belgium Pat. No. 829,758.
U.S. Pat. No. 3,781,282 discloses in a teaching example (Example 7) the preparation of cefadroxil by dissolution of a cefadroxil.DMF solvate in acidified water followed by neutralization with triethylamine. There is no indication from this reference that the cefadroxil product would be in the form of a crystalline monohydrate or indeed that it would even be in a crystalline form.
In view of the many important advantages of cefadroxil, it is desirable to have a commercially useful process for preparing this antibiotic in higher yields and with lower production costs than afforded by the prior art processes. Additionally, it is desirable to provide cefadroxil in a stable crystalline form such as a crystalline hydrate which would enable the antibiotic to be prepared into suitable pharmaceutical formulations for antibacterial use.